Radical SAM enzymes belong to a superfamily of enzymes that use an iron-sulfur cluster ( 4Fe-4S) to reductively cleave ''S''-adenosyl-L-methionine (SAM) to generate a

radical Radical (from Latin: ', root) may refer to: Politics and ideology Politics *Classical radicalism, the Radical Movement that began in late 18th century Britain and spread to continental Europe and Latin America in the 19th century *Radical politics ...

, usually a 5′- deoxyadenosyl radical (5'-dAdo), as a critical intermediate. These enzymes utilize this radical intermediate to perform diverse transformations, often to functionalize unactivated C-H bonds. Radical SAM enzymes are involved in cofactor biosynthesis, enzyme activation,

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

modification, post-transcriptional and

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

metalloprotein Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains al ...

cluster formation,

tRNA Transfer ribonucleic acid (tRNA), formerly referred to as soluble ribonucleic acid (sRNA), is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes). In a cell, it provides the physical link between the gene ...

modification, lipid metabolism, biosynthesis of antibiotics and natural products etc. The vast majority of known radical SAM enzymes belong to the radical SAM superfamily, and have a

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

-rich motif that matches or resembles CxxxCxxC. Radical SAM enzymes comprise the largest superfamily of metal-containing enzymes.

History and mechanism

As of 2001, 645 unique radical SAM enzymes have been identified from 126 species in all three domains of life. According to the EFI and SFLD databases, more than 220,000 radical SAM enzymes are predicted to be involved in 85 types of biochemical transformations. The mechanism for these reactions entail transfer of a methyl or adenosyl group from sulfur to iron. The resulting organoiron complex subsequently releases the organic radical. The latter step is reminiscent of the behavior of adenosyl and methyl cobalamins.

Nomenclature

All enzymes including radical SAM enzymes follow an easy guideline for systematic naming. Systematic naming of enzymes allows a uniform naming process that is recognized by all scientists to understand corresponding function. The first word of the enzyme name often shows the

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...

of the enzyme. The position of the reaction on the substrate will also be in the beginning portion of the name. Lastly, the class of the enzyme will be described in the other half of the name which will end in suffix -ase. The class of an enzyme will describe what the enzyme is doing or changing on the substrate. For example, a ligase combines two molecules to form a new bond. RadicalSAMcoredomain front back

Reaction classification

Representative enzymes will be mentioned for each class. Radical SAM enzymes and their mechanisms known before 2008 are summarized by Frey ''et al''. Since 2015, additional review articles on radical SAM enzymes are available, including: # Advances in Radical SAM Enzymology: New Structures and Mechanisms: # Radical S-Adenosylmethionine Enzymes: # Radical S-Adenosylmethionine (SAM) Enzymes in Cofactor Biosynthesis: A Treasure Trove of Complex Organic Radical Rearrangement Reactions: # Molecular architectures and functions of radical enzymes and their proteins: # Radical SAM enzymes in RiPP biosynthesis. # Radical SAM enzymes with a vitamin B₁₂ (cobalamin)-binding domain.

Carbon methylation

Radical SAM methylases/methyltransferases are one of the largest yet diverse subgroups and are capable of methylating a broad range of unreactive carbon and phosphorus centers. These enzymes are divided into three classes (Class A, B and C) with representative methylation mechanisms. The shared characteristic is the usage of SAM, split into two distinct roles: one as a source of a methyl group donor, and the second as a source of 5'-dAdo radical. Another class has been proposed (class D) but proved to be wrongly assigned.

Class A sub-family

* Class A enzymes methylate specific

adenosine Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9- glycosidic bond. Adenosine is one of the four nucleoside build ...

residues on

rRNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...

and/or tRNA. In other words, they are RNA base-modifying radical SAM enzymes. * The most mechanistically well-characterized are enzymes RlmN and Cfr. Both enzymes methylates substrate by adding a methylene fragment originating from SAM molecule. Therefore, RlmN and Cfr are considered methyl synthases instead of methyltransferases.

Class B sub-family

* Class B enzymes are the largest and most versatile which can methylate a wide range of carbon and phosphorus centers. * These enzymes require a cobalamin (

vitamin B12 Vitamin B12, also known as cobalamin, is a water-soluble vitamin involved in metabolism. One of eight B vitamins, it serves as a vital cofactor (biochemistry), cofactor in DNA synthesis and both fatty acid metabolism, fatty acid and amino a ...

) cofactor as an intermediate methyl group carrier to transfer a methyl group from SAM to substrate. * One well-investigated representative enzyme is TsrM which involves in

tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromat ...

methylation in thiostrepton biosynthesis.

Class C sub-family

* Class C enzymes are reported to play roles in biosynthesis of complex natural products and secondary metabolites. These enzymes methylate heteroaromatic substrates and are cobalamin-independent. * These enzymes contain both the radical SAM motif and exhibit striking sequence similarity to coproporhyrinogen III oxidase (HemN), a radical SAM enzyme involved in heme biosynthesis * Detailed mechanistic investigations on two class C radical SAM methylases have been reported: *# TbtI is involved in the biosynthesis of potent thiopeptide antibiotic thiomuracin. *# Jaw5 is suggested to be responsible for

cyclopropane Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a triangular ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane ...

modifications.

Methylthiolation of tRNAs

Methylthiotransferases belong to a subset of radical SAM enzymes that contain two Fe-4Ssup>+ clusters and one radical SAM domain. Methylthiotransferases play a major role in catalyzing methylthiolation on tRNA nucleotides or anticodons through a redox mechanism. Thiolation modification is believed to maintain translational efficiency and fidelity. MiaB and RimO are both well-characterized and bacterial prototypes for tRNA-modifying methylthiotransferases * MiaB introduces a methylthio group to the isopentenylated A37 derivatives in the tRNA of ''S.'' Typhimurium and ''

E. coli ''Escherichia coli'' ( )Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. is a gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escherichia'' that is commonly foun ...

'' by utilizing one SAM molecule to generate 5'-dAdo radical to activate the substrate and a second SAM to donate a sulfur atom to the substrate. * RimO is responsible for post-translational modification of Asp88 of the ribosomal protein S12 in ''E. coli''. The crystal structure sheds light on the mechanistic action of RimO. The enzyme catalyzes pentasulfide bridge formation linking two Fe-S clusters to allow for sulfur insertion to the substrate. eMtaB is the designated methylthiotransferase in eukaryotic and archaeal cells. eMtaB catalyzes the methylthiolation of tRNA at position 37 on N6-threonylcarbamoyladenosine. A bacterial homologue of eMtaB, YqeV has been reported and suggested to function similarly to MiaB and RimO.

Sulfur insertion into unreactive C-H bonds

Sulfurtransferases are a small subset of radical SAM enzymes. Two well-known examples are BioB and LipA which are independently responsible for biotin synthesis and lipoic acid metabolism, respectively. * BioB or biotin synthase is a radical SAM enzyme that employs one Fe-4Scenter to thiolate dethiobitin, thus converting it to

biotin Biotin (also known as vitamin B7 or vitamin H) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. ...

or also known as vitamin B7.

Vitamin B7 Biotin (also known as vitamin B7 or vitamin H) is one of the B vitamins. It is involved in a wide range of metabolic processes, both in humans and in other organisms, primarily related to the utilization of fats, carbohydrates, and amino acids. ...

is a cofactor used in

carboxylation Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymously with carboxylation ...

decarboxylation Decarboxylation is a chemical reaction that removes a carboxyl group and releases carbon dioxide (CO2). Usually, decarboxylation refers to a reaction of carboxylic acids, removing a carbon atom from a carbon chain. The reverse process, which is ...

, and transcarboxylation reactions in many organisms. * LipA or lipoyl synthase is radical SAM sulfurtransferase utilizing two Fe-4Sclusters to catalyze the final step in lipoic acid biosynthesis.

Carbon insertion

The active site of Mo

nitrogenase Nitrogenases are enzymes () that are produced by certain bacteria, such as cyanobacteria (blue-green bacteria) and rhizobacteria. These enzymes are responsible for the reduction of nitrogen (N2) to ammonia (NH3). Nitrogenases are the only fa ...

is the M-cluster, a metal-sulfur cluster containing a carbide at its core. Within the biosynthesis of M-cluster, radical SAM enzyme NifB has been recognized to catalyze a carbon insertion reaction, leading to formation of a Mo/homocitrate-free precursor of M-cluster.

Anaerobic oxidative decarboxylation

* One well-studied example is HemN. HemN or anaerobic coproporphyrinogen III oxidase is a radical SAM enzyme that catalyzes the oxidative decarboxylation of coproporphyrinogen III to protoporhyrinogen IX, an intermediate in heme biosynthesis. Evidence support the idea that HemN utilizes two SAM molecules to mediate radical-mediated hydrogen transfer for the sequential decarboxylation of the two propionate groups of coproporphyrinogen III. * Hyperthermophilic sulfate-reducing archaen '' Archaeoglobus fulgidus'' enables anaerobic oxidation of long chain ''n''-alkanes. PflD is reported to be responsible for the capacity of ''A. fulgidus'' to grow on a wide range of unsaturated carbons and fatty acids. A detailed biochemical and mechanistic characterization of PflD is still undergoing but preliminary data suggest PflD may be a radical SAM enzyme.

Protein post-translational modification

* Formyl-glycine dependent sulfatases require the critical post-translational modification of an active site cysteine or serine residue into a Cα-formylglycine. A radical SAM enzyme called anSME catalyze this post-translational modification in an oxygen-independent manner.

Protein radical formation

Glycyl radical enzyme activating enzymes (GRE-AEs) are radical SAM subset that can house a stable and catalytically essential glycyl radical in their active state. The underlying chemistry is considered to be the simplest in the radical SAM superfamily with H-atom abstraction by the 5'-dAdo radical being the product of the reaction. A few examples include: * Pyruvate formate-lyase activating enzyme (PFL-AE) catalyzes the activation of PFL, a central enzyme in anaerobic glucose metabolism in microbes. * Benzylsuccinate synthase (BSS) is a central enzyme in anaerobic

toluene Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon with the chemical formula , often abbreviated as , where Ph stands for the phenyl group. It is a colorless, water Water is an inorganic compound with the c ...

catabolism Catabolism () is the set of metabolic pathways that breaks down molecules into smaller units that are either oxidized to release energy or used in other anabolic reactions. Catabolism breaks down large molecules (such as polysaccharides, lipid ...

Peptide modifications

Radical SAM enzymes that can catalyze sulfur-to-alpha carbon thioether cross-linked peptides (sactipeptides) generate a class of peptide with antibacterial properties. These peptides belong to the emerging class of

ribosomally synthesized and post-translationally modified peptides Ribosomally synthesized and post-translationally modified peptides (RiPPs), also known as ribosomal natural products, are a diverse class of natural products of ribosomal origin. Consisting of more than 20 sub-classes, RiPPs are produced by a vari ...

(RiPPs). Another subset of peptide-modifying radical SAM enzymes is SPASM/Twitch domain-carrying enzymes. SPASM/Twitch enzymes carry a functionalized C-terminal extension for the binding of two Fe-4Sclusters, especially in post-translational modifications of peptides. The following examples are representative enzymes that can catalyze peptide modifications to generate specific natural products or cofactors. # TsrM in thiostrepton biosynthesis # PoyD and PoyC in polytheonamide biosynthesis # TbtI in thiomuracin biosynthesis # NosN in nosiheptide biosynthesis #EpeE (previously called YydG) in biosynthesis # MoaA in

molybdopterin Molybdopterins are a class of cofactors found in most molybdenum-containing and all tungsten-containing enzymes. Synonyms for molybdopterin are: MPT and pyranopterin-dithiolate. The nomenclature for this biomolecule can be confusing: Molybdopte ...

biosynthesis # PqqE in pyrroloquinoline quinone biosynthesis # TunB in tunicamycin biosynthesis # OxsB in oxetanocin biosynthesis # BchE in anaerobic

bacteriochlorophyll Bacteriochlorophylls (BChl) are photosynthetic pigments that occur in various phototrophic bacteria. They were discovered by C. B. van Niel in 1932. They are related to chlorophylls, which are the primary pigments in plants, algae, and cyanobacte ...

biosynthesis # F0 synthases in F420 cofactor biosynthesis # MqnE and MqnC in

menaquinone Vitamin K2 or menaquinone (MK) () is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone) and K3 (menadione). K2 is both a tissue and bacterial product (derived from vitamin K1 in both cases) and is usually found in an ...

biosynthesis # QhpD in post-translational processing of quinohemoprotein amine dehydrogenase #RumMC2 in ruminococcin C biosynthesis

Epimerization

Radical SAM epimerases are responsible for the

regioselective In organic chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a str ...

introduction of D-amino acids into RiPPs. Two well-known enzymes have been thoroughly described in RiPP biosynthetic pathways. Radical SAM peptide epimerases use a critical cysteine residue to provide back an H-atom to the epimerized residue in addition to unique features for RiPP interaction. Two well-known enzymes have been thoroughly described in RiPP biosynthetic pathways. * PoyD installs numerous D-stereocenters in enzyme PoyA to ultimately help facilitate polytheonamide biosynthesis. Polytheoamide is a natural potent cytoxic agent by forming pores in membranes. This peptide cytotoxin is naturally produced by uncultivated bacteria that exist as symbionts in a marine sponge. * YydG (EpeE) epimerase modifies two amino acid positions on YydF in Gram-positive ''

Bacillus subtilis ''Bacillus subtilis'' (), known also as the hay bacillus or grass bacillus, is a gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacill ...

''. Extrinsically added YydF mediates subsequent dissipation of membrane potential via membrane permeabilization, resulting in death of the organism. The structure of this enzyme also proved to be unique among RiPP-modifying enzymes.

Complex carbon skeleton rearrangements

Another subset of radical SAM superfamily has been shown to catalyze carbon skeleton rearrangements especially in the areas of DNA repair and cofactor biosynthesis. * DNA spore photoproduct lysase (SPL) is a radical SAM that can repair DNA

thymine dimers Pyrimidine dimers represent molecular lesions originating from thymine or cytosine bases within DNA, resulting from photochemical reactions. These lesions, commonly linked to direct DNA damage, are induced by ultraviolet light (UV), particularly ...

(spore product, SP) caused by UV radiation. Despite the remaining unknowns and controversies involving SPL-catalyzed reaction, it is certain that SPL utilizes SAM as a cofactor to generate 5'-dAdo radical to revert SP to two thymine residues. * HydG is a radical SAM responsible for generating CO and CN⁻ ligands in the e-Fehydrogenase (HydA) in various anaerobic bacteria. * Radical SAM MoaA and MoaC are involved in converting GTP into cyclic pyranopterin monophosphate (cPMP). Overall, both play roles in

biosynthesis.

Other reactions

* A radical SAM enzyme with intrinsic lyase activity is able to catalyze lysine transfer reaction, generating archaea-specific archaosine-containing tRNAs. * Viperin is an interferon-stimulated radical SAM enzyme which converts CTP to ddhCTP (3ʹ-deoxy-3′,4ʹdidehydro-CTP), which is a chain terminator for viral RdRps and therefore a natural antiviral compound.

Clinical considerations

* Deficiency in human tRNA methylthiotransferase eMtaB has been shown to be responsible for abnormal insulin synthesis and predisposition to

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

. * Mutations in human GTP cyclase MoaA has been reported to lead to molybdenum cofactor deficiency, a usually fatal disease accompanied by severe neurological symptoms. * Mutations in human wybutosine-tRNA modifying enzyme Tyw1 promotes

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase e ...

infection. * Alterations in human tRNA-modifying enzyme Elp3 results in progression into

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

(ALS). * Mutations in human antiviral RSAD1 has been shown to be associated with congenital heart disease. * Mutations in human sulfurtransferase LipA has been implicated in

glycine encephalopathy Glycine encephalopathy is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleav ...

pyruvate dehydrogenase Pyruvate dehydrogenase is an enzyme that catalyzes the reaction of pyruvate and a lipoamide to give the acetylated dihydrolipoamide and carbon dioxide. The conversion requires the coenzyme thiamine pyrophosphate. Pyruvate dehydrogenase is ...

and lipoic acid synthetase deficiency. * Mutations in human methylthiotransferase MiaB are related to impaired cardiac and respiratory functions.

Therapeutic applications

Below are a few examples of radical SAM enzymes have been shown to be promising targets for antibiotic and antiviral development. * Inhibition of radical SAM enzyme MqnE in menaquinone biosynthesis is reported to be an effective antibacterial strategy against '' H. pylori''. * Radical SAM enzyme BlsE has been discovered to be a central enzyme in blasticidin S biosynthetic pathway. Blasticidin S produced by '' Streptomyces griseochromogenes'' exhibits strong inhibitory activity against rice blast caused by '' Pyricularia oryzae'' Cavara. This compound specifically inhibits protein synthesis in both prokaryotes and eukaryotes through inhibition of peptide bond formation in the ribosome machinery. * A new fungal radical SAM enzyme has also been reported to facilitate the biocatalytic routes for synthesis of 3'-deoxy nucleotides/nucleosides. 3'deoxynucleotides are a class of drugs that interfere with the metabolism of nucleotides, and their incorporation into DNA or RNA terminates cell division and replication. This activity explains why this compound is an essential group of antiviral, antibacterial or anticancer drug.

Examples

Examples of radical SAM enzymes found within the radical SAM superfamily include: * AblA -

lysine 2,3-aminomutase Lysine 2,3-aminomutase (KAM or LAM) () is a radical SAM enzyme that facilitates the conversion of the Amino Acid, amino acid lysine to beta-lysine. It accomplishes this interconversion using three Cofactor (biochemistry), cofactors and a 5'-deoxyad ...

(

osmolyte Osmolytes are low-molecular-weight organic compounds that influence the properties of biological fluids. Osmolytes are a class of organic molecules that play a significant role in regulating osmotic pressure and maintaining cellular homeostasis in ...

biosynthesis - N-epsilon-acetyl-beta-lysine) * AlbA - subtilosin maturase (peptide modification) * AtsB - anaerobic sulfatase activase (enzyme activation) * BchE - anaerobic magnesium protoporphyrin-IX oxidative cyclase (cofactor biosynthesis -

chlorophyll Chlorophyll is any of several related green pigments found in cyanobacteria and in the chloroplasts of algae and plants. Its name is derived from the Greek words (, "pale green") and (, "leaf"). Chlorophyll allows plants to absorb energy ...

) * BioB - biotin synthase (cofactor biosynthesis -

) * BlsE - cytosylglucuronic acid decarboxylase - blasticidin S biosynthesis * BtrN - butirosin biosynthesis pathway oxidoreductase (

aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...

antibiotic biosynthesis) * BzaF - 5-hydroxybenzimidazole (5-HBI) synthesis (cobalt binding ligand of cobalamin) * Cfr - 23S rRNA (adenine(2503)-C(8))-methyltransferase - rRNA modification for

antibiotic resistance Antimicrobial resistance (AMR or AR) occurs when microbes evolve mechanisms that protect them from antimicrobials, which are drugs used to treat infections. This resistance affects all classes of microbes, including bacteria (antibiotic resis ...

* CofG - FO synthase, CofG subunit (cofactor biosynthesis - F420) * CofH - FO synthase, CofH subunit (cofactor biosynthesis - F420) * CutD - trimethylamine lyase-activating enzyme * DarE - darobactin maturase * DesII - D-desosamine biosynthesis deaminase (sugar modification for

macrolide Macrolides are a class of mostly natural products with a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. Macrolides belong to the polyketide class of natural products. ...

antibiotic biosynthesis) * EpeE - biosynthesis of epipeptide (RiPP) * EpmB - elongation factor P beta-lysylation protein (protein modification) * HemN - oxygen-independent coproporphyrinogen III oxidase (cofactor biosynthesis -

heme Heme (American English), or haem (Commonwealth English, both pronounced /Help:IPA/English, hi:m/ ), is a ring-shaped iron-containing molecule that commonly serves as a Ligand (biochemistry), ligand of various proteins, more notably as a Prostheti ...

) * HmdB - 5,10-methenyltetrahydromethanopterin hydrogenase cofactor biosynthesis protein HmdB (note unusual CX5CX2C motif) * HpnR - hopanoid C-3 methylase (lipid biosynthesis - 3-methylhopanoid production) * HydE -

eFe Agencia EFE, S.A. () is a Spanish international news agency, the major Spanish language, Spanish-language multimedia news agency and the world's fourth largest wire service after the Associated Press, Reuters, and Agence France-Presse. EFE was ...

hydrogenase A hydrogenase is an enzyme that Catalysis, catalyses the reversible Redox, oxidation of molecular hydrogen (H2), as shown below: Hydrogen oxidation () is coupled to the reduction of electron acceptors such as oxygen, nitrate, Ferric, ferric i ...

H-cluster radical SAM maturase (metallocluster assembly) * HydG -

hydrogenase H-cluster radical SAM maturase (metallocluster assembly) * LipA - lipoyl synthase (cofactor biosynthesis - lipoyl) * MftC - mycofactocin system maturase (peptide modification/cofactor biosynthesis - predicted) * MiaB - tRNA methylthiotransferase (

modification) * Mmp10 - methyl-coenzyme M reductase (MCR) post-translational modification * MoaA - GTP 3',8-cyclase (cofactor biosynthesis -

) * MqnC - dehypoxanthine futalosine cyclase (cofactor biosynthesis -

via futalosine) * MqnE - aminofutalosine synthase (cofactor biosynthesis - menaquinone via futalosine) * NifB - cofactor biosynthesis protein NifB (cofactor biosynthesis - FeMo cofactor) * NirJ - heme d1 biosynthesis radical SAM protein NirJ (cofactor biosynthesis - heme d1) * NosL - complex rearrangement of tryptophan to 3-methyl-2-indolic acid - nosiheptide biosynthesis * NrdG - anaerobic ribonucleoside-triphosphate reductase activase (enzyme activation) * PflA - pyruvate formate-lyase activating enzyme (enzyme activation) * PhpK - radical SAM P-methyltransferase - antibiotic biosynthesis * PqqE - PQQ biosynthesis enzyme (peptide modification / cofactor biosynthesis - PQQ) * PylB - methylornithine synthase, pyrrolysine biosynthesis protein PylB (amino acid biosynthesis -

pyrrolysine Pyrrolysine (symbol Pyl or O), encoded by the 'amber' stop codon UAG, is a proteinogenic amino acid that is used in some methanogenic archaea and in bacteria. It consists of lysine with a 4-methylpyrroline-5-carboxylate in amide linkage with the ...

) * QhpD (PeaB) - quinohemoprotein amine dehydrogenase maturation protein (enzyme activation) * QueE - 7-carboxy-7-deazaguanine (CDG) synthase * RimO - ribosomal protein S12 methylthiotransferase * RlmN - 23S rRNA (adenine(2503)-C(2))-methyltransferase (

modification) * ScfB - SCIFF maturase (peptide modification by thioether cross-link formation) * SkfB - sporulation killing factor maturase * SplB - spore photoproduct lyase (

DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...

) * ThiC - 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMP-P) biosynthesis (cofactor biosynthesis - thiamine) * ThiH - thiazole phosphate biosynthesis (cofactor biosynthesis -

thiamine Thiamine, also known as thiamin and vitamin B1, is a vitamin – an Nutrient#Micronutrients, essential micronutrient for humans and animals. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosp ...

) * TrnC - thuricin biosynthesis * TrnD - thuricin biosynthesis * TsrT - tryptophan 2-C-methyltransferase (amino acid modification - antibiotic biosynthesis) * TYW1 - 4-demethylwyosine synthase (

modification) * YqeV - tRNA methylthiotransferase (

modification)

Non-canonical

In addition, several non-canonical radical SAM enzymes have been described. These cannot be recognized by the

Pfam Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The latest version of Pfam, 37.0, was released in June 2024 and contains 21,979 families. It is cur ...

hidden Markov model A hidden Markov model (HMM) is a Markov model in which the observations are dependent on a latent (or ''hidden'') Markov process (referred to as X). An HMM requires that there be an observable process Y whose outcomes depend on the outcomes of X ...

PF04055, but still use three Cys residues as ligands to a 4Fe4S cluster and produce a radical from S-adenosylmethionine. These include * ThiC (PF01964) - thiamine biosynthesis protein ThiC (cofactor biosynthesis - thiamine) (Cys residues near extreme C-terminus) * Dph2 (PF01866) - diphthamide biosynthesis enzyme Dph2 (protein modification -

diphthamide Diphthamide is a post-translationally modified histidine amino acid found in archaeal and eukaryotic elongation factor 2 (eEF-2). Dipthamide is named after the toxin produced by the bacterium ''Corynebacterium diphtheriae'', which targets diphth ...

in translation elongation factor 2) (note different radical production, a 3-amino-3-carboxypropyl radical) * PhnJ (PF06007) - phosphonate metabolism protein PhnJ (C-P

phosphonate In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing Functional group, groups, where R is an organic group (alkyl, aryl). If R is hydrogen then the compound is a Phosphite_ester#Chemistry_of_HP(O)(OR ...

bond cleavage)

References

{{Reflist, 32em

External links

Structure Function Linkage Database (SFLD) List of Reactions
Enzymes